Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 25 July 2017

Indication(s)

1 INDICATIONS AND USAGE Tretinoin Gel Microsphere, 0.1% and 0.04%, is a retinoid indicated for topical application in the treatment of acne vulgaris. Tretinoin Gel Microsphere, 0.1% and 0.04%, is a retinoid, indicated for topical treatment of acne vulgaris. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions are skin pain, pruritus, skin irritation/subcutaneous irritation, pharyngitis, and erythema. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Spear Dermatology Products at 1-866-SPEAR-RX (773-2779) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Subjects with Acne In separate clinical trials for each concentration, acne subjects treated with Tretinoin Gel Microsphere, 0.1% or 0.04%, over the twelve week period showed that cutaneous irritation scores for erythema, peeling, dryness, burning/stinging, or itching peaked during the initial two weeks of therapy, decreasing thereafter. Approximately half of the subjects treated with Tretinoin Gel Microsphere, 0.04% had cutaneous irritation at Week 2. Of those subjects who did experience cutaneous side effects, most had signs or symptoms that were mild in severity (severity was ranked on a 4-point ordinal scale: 0=none, 1=mild, 2=moderate, and 3=severe). Less than 10% of patients experienced moderate cutaneous irritation and there was no severe irritation at Week 2. In trials of Tretinoin Gel Microsphere, 0.04%, throughout the treatment period the majority of subjects experienced some degree of irritation (mild, moderate, or severe) with 1% (2/225) of subjects having scores indicative of a severe irritation; 1.3% (3/225) of subjects treated with Tretinoin Gel Microsphere, 0.04%, discontinued treatment due to irritation, which included dryness in one patient and peeling and urticaria in another. In trials of Tretinoin Gel Microsphere, 0.1%, no more than 3% of subjects had cutaneous irritation scores indicative of severe irritation; 6% (14/224) of subjects treated with Tretinoin Gel Microsphere, 0.1% discontinued treatment due to irritation. Of these 14 subjects, four had severe irritation after 3 to 5 days of treatment, with blistering in one subject. In a double-blind trial with 156 acne subjects comparing 12 weeks of treatment with Tretinoin Gel Microsphere, 0.04% or 0.1% (78 subjects each group), the most frequently-reported adverse events affected the skin and subcutaneous tissue (15.4% in the 0.04% group, and 20.5% in the 0.1% group). The most prevalent of the dermatologic adverse events in the 0.04% group was skin irritation (6.4%); and in the 0.1% group skin burning (7.7%), erythema (5.1%), skin irritation (3.8%), and dermatitis (3.8%). Most adverse events were of mild intensity (63.4%), and 34.4% were moderate. One subject in each group had adverse events characterized as severe, neither were dermatologic findings and neither was characterized as related to drug by the investigator. Trials in Subjects Without Acne In a half-face comparison trial conducted for up to 14 days in women with sensitive skin, but without acne, Tretinoin Gel Microsphere, 0.1% was statistically less irritating than tretinoin cream, 0.1%. In addition, a cumulative 21 day irritation evaluation in subjects with normal skin showed that Tretinoin Gel Microsphere, 0.1%, had a lower irritation profile than tretinoin cream, 0.1%. The clinical significance of these irritation studies for patients with acne is not established. Comparable effectiveness of Tretinoin Gel Microsphere, 0.1% and tretinoin cream, 0.1%, has not been established. The lower irritancy of Tretinoin Gel Microsphere, 0.1% in subjects without acne may be attributable to the properties of its vehicle. The contribution of decreased irritancy by the MICROSPONGE System has not been established. No irritation trials have been performed to compare Tretinoin Gel Microsphere, 0.04%, with either Tretinoin Gel Microsphere, 0.1%, or tretinoin cream, 0.1%. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Tretinoin Gel Microsphere. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION For topical use only. Not for ophthalmic, oral, or intravaginal use. Tretinoin Gel Microsphere, 0.1% and 0.04%, should be applied once a day, in the evening, to the skin where acne lesions appear, using enough to cover the entire affected area in a thin layer. Areas to be treated should be cleansed thoroughly before the medication is applied. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. A transitory feeling of warmth or slight stinging may be noted on application. In cases where it has been necessary to temporarily discontinue therapy or to reduce the frequency of application, therapy may be resumed or the frequency of application increased as the patient becomes able to tolerate the treatment. Frequency of application should be closely monitored by careful observation of the clinical therapeutic response and skin tolerance. Efficacy has not been established for less than once daily dosing frequencies. During the early weeks of therapy, an apparent exacerbation of inflammatory lesions may occur. If tolerated, this should not be considered a reason to discontinue therapy [see Adverse Reactions (6.1)]. Therapeutic results may be noticed after two weeks, but more than seven weeks of therapy are required before consistent beneficial effects are observed. Tretinoin Gel Microsphere, 0.1% and 0.04%, should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. Patients treated with Tretinoin Gel Microsphere, 0.1% and 0.04% may use cosmetics. Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Tretinoin Gel Microsphere, 0.1% and 0.04%. It also is advisable to allow the effects of such preparations to subside before use of Tretinoin Gel Microsphere, 0.1% and 0.04%, is begun. • Apply a thin layer of Tretinoin Gel Microsphere once daily, before bedtime, to skin where lesions occur. Keep away from eyes, mouth, nasal creases, and mucous membranes. (2) • Not for oral, ophthalmic, or intravaginal use. (2)
Use in special populations
8 USE IN SPECIFIC POPULATIONS Tretinoin Gel Microsphere should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no adequate and well-controlled studies in pregnant and nursing women. (8.1) 8.1 Pregnancy There are no adequate and well-controlled studies in pregnant women. Tretinoin Gel Microsphere should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of Tretinoin Gel Microsphere, 0.1% and 0.04%. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. For purposes of comparison of the animal exposure to systemic human exposure, the Maximum Recommended Human Dose (MRHD) applied topically is defined as 1 gram of Tretinoin Gel Microsphere, 0.1% applied daily to a 60 kg person (0.017 mg tretinoin/kg body weight). Pregnant rats were treated with Tretinoin Gel Microsphere, 0.1%, at daily dermal doses of 0.5 to 1 mg/kg/day on gestation days 6-15. Alterations were seen in vertebrae and ribs of offspring at 5 to 10 times the MRHD based on the body surface area (BSA) comparison. Pregnant New Zealand White rabbits were treated with Tretinoin Gel Microsphere, 0.1%, at daily dermal doses of 0.2, 0.5, and 1.0 mg/kg/day tretinoin on gestation days 7-19. Doses were administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. Increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, were observed at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 4 times the MRHD based on BSA comparison. Other pregnant rabbits exposed topically for six hours per day to 0.5 or 1.0 mg/kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any teratogenic effects at doses up to 19 times (1.0 mg/kg/day) the MRHD based on BSA comparison, but fetal resorptions were increased at 0.5 mg/kg (10 times the MRHD based on BSA comparison). Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and nonhuman primates. Tretinoin was teratogenic in Wistar rats when given orally in doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day but none were observed at 5 mg/kg/day (95 times the MRHD based on BSA comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (10 times the MRHD based on BSA comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids. In oral peri- and postnatal development studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (19 times the MRHD based on BSA comparison). Nonteratogenic effects on fetus Oral tretinoin has been shown to be fetotoxic when administered (in doses 24 times the MRHD based on BSA comparison). Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses 10 times the MRHD based on BSA comparison. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Tretinoin Gel Microsphere, 0.1% or 0.04%, is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in children below the age of 12 have not been established. 8.5 Geriatric Use Safety and effectiveness in a geriatric population have not been established. Clinical trials of Tretinoin Gel Microsphere, 0.1% and 0.04% did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects.

More information

Category Value
Authorisation number NDA020475
Agency product number 5688UTC01R
Orphan designation No
Product NDC 66530-260,66530-259
Date Last Revised 01-09-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 313453
Marketing authorisation holder Spear Dermatology Products Inc